Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening

This randomized clinical trial compared use of a biomarker-based strategy vs a magnetic resonance imaging–enhanced strategy for detection of clinically significant prostate cancer among men in Sweden.


Introduction
Population-based screening with a prostate-specific antigen (PSA) test has been shown to reduce mortality in prostate cancer. 1 However, the PSA test has limited sensitivity and specificity, resulting in missed early detection of significant cancers, unnecessary biopsies, and detection of indolent cancers.3][4][5] Current guidelines from the European Association of Urology 6 and the National Comprehensive Cancer Network 7 recommend obtaining an MRI of the prostate before diagnostic biopsy.The American Urological Association 8 considers MRI optional before initial prostate biopsy but recommends an MRI for men with a previous negative biopsy result.
Nevertheless, MRI-based screening for prostate cancer presents challenges.The procedure is technically complex, patient access may vary, and most studies have been conducted at specialized centers with extensive experience in MRI of the prostate, which raises concerns about the generalizability of findings across diverse settings.0][11] Furthermore, there is ongoing debate about whether the pathological evaluation of targeted biopsy specimens should differ from that of systematic biopsy specimens given the potential for Gleason score inflation due to increased detection with targeted biopsy, with unclear long-term clinical implications. 12,135][16][17][18] These tests incorporate parameters such as genetic markers, PSA-related markers, and clinical variables.One such test, the blood-based Stockholm3 test, combines patient age, previous prostate biopsy results, family history of prostate cancer, single-nucleotide variations (formerly single-nucleotide polymorphisms), and levels of total PSA, free PSA, human kallikrein 2, β-microseminoprotein, and growth differentiation factor 15 to estimate the risk of clinically significant cancer (Gleason score Ն3 + 4).The Stockholm3 test was designed to detect clinically significant prostate cancer as well as PSA levels of 3 ng/mL or higher (to convert to micrograms per liter, multiply by 1), and a prospective population-based study found that the test could achieve this goal while reducing the number of biopsies performed and detection of clinically insignificant cancers. 16Additionally, Nordström et al 19 showed within the MRI-enhanced group of the STHLM3-MRI trial that using the Stockholm3 and PSA tests in combination to determine which men should undergo MRI substantially reduced the number of MRIs and biopsies performed without compromising the detection of clinically significant prostate cancer.

Study Design
The STHLM3-MRI trial was a population-based randomized clinical trial that used both paired and randomized designs to facilitate comparisons of multiple strategies for diagnosing prostate cancer.
The study was conducted in Stockholm, Sweden, from April 4, 2018, to December 10, 2020.Detailed study methods have been published. 20Men aged 50 to 74 years who were residents of Stockholm

Randomization
After baseline assessment, men with an elevated risk of prostate cancer (PSA level Ն3 ng/mL or Stockholm3 risk score Ն0.11) were randomly assigned in a 2:3 ratio to either the biomarker group or the MRI-enhanced group.Initally, men in the biomarker group with a Stockholm3 score of 0.11 or higher were referred for systematic biopsies.In the MRI-enhanced group, men whose PSA level was 3 ng/mL or higher were referred for MRI with targeted or systematic biopsies if they had a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or higher (considered as positive MRI results).The PI-RADS is used to assess the likelihood of clinically significant prostate cancer for each lesion on a scale of 1 (very low) to 5 (very high).
Randomization lists were generated in blocked sequences that were stratified by sextiles for the risk of significant prostate cancer based on Stockholm3 risk score, with a block size of 5.The study biostatistician (A.D.) prepared the randomization lists, and participants were assigned to study groups by the database administrator.Subsequently, men without elevated PSA levels or Stockholm3 risk scores were also randomly assigned to the biomarker or MRI-enhanced groups (Figure 1).
Participants and treating clinicians were not blinded to group assignment.

Intervention
To analyze PSA levels and Stockholm3 risk scores, 12 mL of blood was collected in EDTA-containing tubes at 1 of 60 laboratories in Stockholm and sent to a central laboratory (A3P Biomedical, Uppsala, Sweden) for analysis.The PSA samples were analyzed using the BRAHMS Kryptor Compact Plus analyzer (Thermo Fisher Scientific).The Stockholm3 risk algorithm did not include measurement of prostate volume or performance of a digital rectal examination.
Experienced urologists performed systematic prostate biopsies using transrectal ultrasonography, obtaining 10 to 12 biopsy cores from the peripheral zone of the prostate (apical, midgland, and base).Men randomly assigned to the MRI-enhanced group underwent a T2-and diffusion-weighted biparametric MRI protocol involving a 1.5T or 3T scanner without an endorectal coil.Each case was reviewed by at least 2 experienced uroradiologists using PI-RADS, version 2.1 to assess areas suspicious for prostate cancer.An external uroradiologist reviewed 8% (99) of the MRI results.Men with a positive MRI result were referred for MRI-targeted biopsy assisted by dedicated software.No more than 3 areas suspicious for prostate cancer were chosen for targeted transrectal biopsy, with 3 to 4 biopsy cores obtained per area.Additionally, the same urologist performed transrectal systematic biopsies, obtaining 10 to 12 biopsy cores after the targeted procedure.Men with a negative MRI result (ie, PI-RADS score Յ2) did not undergo biopsy unless the Stockholm3 risk score was 0.25 or higher, indicating a high risk of clinically significant cancer.Prostatic tissue biopsy samples were reviewed by an experienced uropathologist, who reported the Gleason score and the extent of cancer (in millimeters) for each biopsy core.

Outcomes
The primary outcome was the detection of clinically significant prostate cancer, defined as a Gleason score of 3 + 4 or higher.Secondary outcomes included the number of biopsies performed, the number of benign biopsies, clinically insignificant cancers detected (Gleason score Յ6), higher-grade

Statistical Analysis
The number of invited participants in the study was based on power calculations for demonstrating noninferiority in detecting clinically significant cancer in men with a PSA level of 3 ng/mL or higher across the study groups, as reported by Eklund et al. 5 The STHLM3-MRI trial incorporated a paired step and a randomized design, allowing for the comparison of multiple diagnostic strategies.The analysis followed the statistical analysis plan in which the comparison of the diagnostic strategies was prespecified and approved by a data safety and monitoring committee.
The Stockholm3 risk score cutoff of 0.15, suggested by Nordström et al 19  proportions were assessed by computing their ratio and are reported as the proportion of men in the biomarker group relative to the MRI-enhanced group.The 95% CIs were calculated by exponentiating the normal-based confidence limits computed on the log scale.For a practical perspective on screening, the numbers of diagnostic tests, biopsy procedures, and diagnosed cases of prostate cancer (low-grade, clinically significant, and high-grade) per 10 000 screened men were calculated by multiplying the proportions derived from the initial analysis by 10 000.
The main analyses were performed in the intention-to-treat population, which included all enrolled and randomly assigned participants.A sensitivity analysis was conducted within a modelbased multiple imputation population, where the primary outcome was imputed when missing.
Another sensitivity analysis ignored biopsy outcomes for men in the MRI-enhanced group with negative MRI findings but who underwent biopsy due to a Stockholm3 risk score of 0.25 or higher.clinically significant prostate cancers would be missed compared with the number missed with the use of PSA-level screening followed by MRI and biopsies (Figure 2).
Using a Stockholm3 risk score cutoff of 0.11 or higher, a greater number of clinically significant prostate cancers was detected compared with the MRI-enhanced approach, although this difference did not reach statistical significance (relative proportion, 1.12; 95% CI, 0.90-1.38).Furthermore, more biopsy procedures were required and a greater number of insignificant cancers was detected with the biomarker-based approach (Table 2).In the case of using PSA level in combination with systematic biopsies, this approach necessitated more biopsies but resulted in a lower detection rate

JAMA Network Open | Oncology
Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening of clinically significant prostate cancer compared with either the Stockholm3 risk score or the MRI-enhanced approach (Table 2).Importantly, none of the strategies in the biomarker-based group detected fewer clinically significant cancers (Gleason score Ն3 + 4) or higher-grade cancers (Gleason score Ն4 + 3) compared with the MRI-enhanced approach.
Detection of clinically significant prostate cancer for the model-based imputation sensitivity analysis did not differ from findings in the intention-to-treat analysis (Table 2).Excluding biopsy outcomes for men in the MRI-enhanced group with negative MRI results but who underwent biopsy because of a Stockholm3 risk score of 0.25 or higher did not alter the results (eTable 1 in Supplement 2).In the MRI-enhanced group, after limiting the analysis to only include outcomes from systematic biopsies in men with positive MRI results, clinically significant prostate cancer was detected in 1.9% of men in the MRI-enhanced group and 2.3% of those in the biomarker group (relative proportion, 1.20; 95% CI, 0.94-1.52)(eTables 2 and 4 and the eFigure in Supplement 2).
For men diagnosed with prostate cancer who underwent radical prostatectomy, the proportions of Gleason scores misclassified between biopsy review and final pathology examination were similar between the groups (40% in the biomarker group vs 38% in the MRI-enhanced group).
While not statistically significant, tumor upgrading was more common in the biomarker group compared with the MRI-enhanced group (33% vs 23%, P = .17)and downgrading was less common (7% vs 14%, P = .15)(Table 3

Figure 1 .
Figure 1.Trial Flowchart Biomarker vs MRI-Enhanced Strategies for Prostate Cancer ScreeningAs interest in prostate cancer screening grows and the limitations of PSA-and MRI-based screening become apparent, there is a need for alternative screening methods.The European Commission recently called on its members to establish organized prostate cancer screening programs.This randomized clinical trial represents an important step in this direction by assessing the effectiveness of blood-based risk estimation along with systematic biopsies and comparing this biomarker-based approach with the established MRI-targeted biopsy approach within a populationbased screening context.

Participant Recruitment and Baseline Assessment
for sensitivity equivalent to that of a PSA level of 3 ng/mL or higher and MRI, was used in this study.Results with the original Stockholm3 cutoff of 0.11 and a PSA level of 3 ng/mL or higher (which is a standard cutoff value for evaluating biopsy specimens) were also included for comparison.For all outcomes, the proportions of men with abnormal blood test results (Stockholm3 risk score Ն0.15 or higher, Stockholm3 risk score Ն0.11, or PSA level Ն3 ng/mL, as appropriate) and with outcomes of interest in the biomarker group and the MRI-enhanced group were calculated.Relative proportions between

Table 2 )
. Per 10 000 screened men, use of a Stockholm3 risk score of 0.15 or higher followed by systematic biopsies would reduce the number of MRI scans by 1100, but 191 additional biopsies would be required to find 65 additional low-grade prostate cancers while 20 To account for potential Gleason score inflation, an alternative model exclusively used outcomes from systematic biopsies for men in the MRI-enhanced group who had undergone both systematic and targeted biopsies.All analyses were conducted using R, version 4.2.3 (R Project for Statistical Computing).Statistical significance was set at 2-sided P < .05.Data were analyzed from September 1 to November 5, 2023.not differ significantly between the 2 groups (Table 1).Additionally, 34 men in the MRI-enhanced group with elevated PSA levels and negative MRI findings underwent systematic biopsies due to having a Stockholm3 risk score of 0.25 or higher.Clinically significant prostate cancer was detected in 2.3% of men (119 of 5134) in the biomarker group (Stockholm3 risk score Ն0.15%) and in 2.5% of men (192 of 7609) in the MRI-enhanced group JAMA Network Open | Oncology Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening JAMA Network Open.2024;7(4):e247131.doi:10.1001/jamanetworkopen.2024.7131(Reprinted) April 22, 2024 5/13 Downloaded from jamanetwork.comby guest on 04/24/2024

Table 1 .
Patient Characteristics a Seven men were not randomly assigned due to laboratory or administrative errors.

Table 2 .
Outcomes of Patients With MRI Examinations, Biopsies, and Prostate Cancer According to Screening Strategies a Welch 2-sample t test.
19d eTable 3 in Supplement 2).As previously reported by Nordström et al,19the area under the curve for detecting clinically significant prostate cancer was 0.76 (95% CI, 0.72-0.80)for the Stockholm3 risk score and 0.60 (95% CI, 0.54-0.65)for the PSA test, both only for men undergoing systematic biopsy.The positive predictive values (PPVs) for detecting clinically significant prostate cancer with a PSA level of 3 ng/mL or higher was 17.6% (106 of 603 patients), 21.3% (145 of 680 patients) with a Stockholm3 risk score of 0.11 or higher, and 28.8% (119 of 413 patients) with a Stockholm3 risk score of 0.15.2. Screening Tests and Prostate Cancer Outcomes for the Different Diagnostic Strategies per 10 000 Screened Men Stockholm3 is a blood-based test for estimating the risk of clinically significant cancer.MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen.Error bars indicate the 95% CIs.To convert PSA to micrograms per liter, multiply by 1.

Table 3 .
Reclassification of Gleason Score Between Initial Biopsy and Final Pathology Report for Men Undergoing Radical Prostatectomy Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening 25.Brant A, Wu X, Prunty M, et al.Variability of prostate MRI charges among U.S. hospital-based facilities.AJR Am J Roentgenol. 2023;220(3):441-442. doi:10.2214/AJR.22.28152 26.Viste E, Vinje CA, Lid TG, et al.Effects of replacing PSA with Stockholm3 for diagnosis of clinically significant prostate cancer in a healthcare system-the Stavanger experience.Scand J Prim Health Care.2020;38(3):315-322.doi:10.1080/02813432.2020.180213927.Vigneswaran HT, Eklund M, Discacciati A, et al; SEPTA STHLM3 Study Group.Stockholm3 validation in a multiethnic cohort for prostate cancer (SEPTA) detection: a multicentered, prospective trial.J Clin Oncol.2024;42(4) (suppl):262.doi:10.1200/JCO.2024.42.4_suppl.26228.Elyan A, Saba K, Sigle A, et al.Prospective multicenter validation of the Stockholm3 test in a central European cohort.Eur Urol Focus.Published online October 7, 2023.doi:10.1016/j.euf.2023.09.016 29.Hao S, Heintz E, Östensson E, et al.Cost-effectiveness of the Stockholm3 test and magnetic resonance imaging in prostate cancer screening: a microsimulation study.Eur Urol.2022;82(1):12-19.doi:10.1016/j.eururo.2021.12.021Relative Proportions of Men with MRI Scans, Biopsies, and Prostate Cancers According to Screening Strategies (Ignoring Biopsy Outcomes for Men in the MRI-Enhanced Group With Negative MRI Results who Underwent Biopsy due to a Stockholm3 Risk Score of 0.25 or Higher) eTable 2. Relative Proportion of Men with MRI Scans, Biopsies, and Prostate Cancers According to Screening Strategies (Only Including Men Who Underwent Systematic Biopsies in the MRI-Enhanced Group) eTable 3. Gleason Score at Biopsy vs at Prostatectomy in Biomarker-Based Group and MRI-Enhanced Group eTable 4. Gleason Score at Systematic Biopsy vs Combined Systematic and Targeted Biopsy for Men in MRI-Enhanced Group who Underwent Both Types of Biopsies eFigure.Gleason Score on Systematic Biopsy vs Combined Systematic and Targeted Biopsy for Men in MRI-Enhanced Group who Underwent Both Types of Biopsies Abbreviations: MRI, magnetic resonance imaging; PSA, prostate-specific antigen.SI conversion: To convert PSA to micrograms per liter, multiply by 1.a Pearson χ 2 test.JAMA Network Open | Oncology